Chronic infections are a major cause of disease and significant efforts are focused on developing prophylactics and therapeutic interventions for HIV, HBV, and HCV infection. Immune responses initially develop during many chronic viral infections, but viral clearance is not achieved. A major reason for lack of immunological control in these instances is CD8 T cell dysfunction. Rather than developing potent immunity, CD8 T cells during chronic infections often lose effector functions and fail to acquire memory properties. The underlying mechanism of these defects remains poorly understood. The main goal of this proposal is to use the mouse model of chronic LCMV infection to define how three levels of regulation, systemic, cellular and transcriptional, affect CD8 T cell dysfunction. To address this question we will: i) investigate the impact of prolonged exposure to antigen versus chronic inflammation on specific CD8 T cell effector functions and memory properties, ii) determine whether inhibitory receptor blockade or restoration of CD4 help reverses CD8 T cell dysfunction and results in self-renewing, protective, memory CD8 T cells, and iii) investigate the role of two transcription factors, eomesodermin (eomes) and blimp-1, in controlling altered CD8 T cell differentiation and poor memory development during chronic infection. This last goal is based on our preliminary gene expression data showing upregulation of eomes and blimp-1 in CD8 T cells during chronic infection and on the known role of these transcription factors in regulating effector CD8 T cell differentiation (eomes) or terminal differentiation of B cells (blimp-1). A major focus of studies at all three levels of regulation is whether dysfunction is reversible or whether an altered differentiation pathway occurs resulting in terminal differentiation of virus specific CD8 T cells during chronic viral infections. Thus, we hypothesize that CD8 T cell dysfunction during chronic viral infections is due to an altered memory CD8 T cell differentiation program that is controlled at the systemic, cellular and transcriptional levels and that becomes progressively less reversible overtime. These studies should help identify the how different pathways regulate specific CD8 T cell properties. Our studies may provide important information for the design of prophylactic vaccines and also may uncover opportunities to develop novel therapeutic interventions for chronic diseases.